Pharmacological Targeting of the 5-HT1, A2A and NMDA Receptors: An Integrative Approach to Dyskinesia
MJFF Research Grant, 2012
The glutamate, serotonin and adenosine systems are interesting targets for pharmacological therapies in Parkinsonīs disease. However, interventions addressed at single systems have so far produced limited results. Indeed, the alterations induced in the human brain by the loss of dopamine neurons are complex and affect the function of several brain systems. In this project we intend to counteract dyskinesia and worsening of motor function by co-targeting the above systems, which is expected to produce a better outcome than individual interventions.
We will use drugs that can be used on humans. The serotonin 5-HT1 receptor against Eltoprazine will be administered with the A2A receptor antagonist Preladenant or the NMDA receptor antagonist Amantadine to counteract dyskinesia and worsening of the therapeutic effect of L-DOPA in the pre-clinical model of Parkinsonīs disease. Moreover, the most promising approach will be tested, during the second year, in the MPTP-treated model, the gold-standard model for pre-clinical studies of Parkinsonīs disease.
Relevance to Diagnosis/Treatment of Parkinsons Disease:
The appearance of dyskinesia represents a serious limitation for management of motor symptoms in advanced stages of disease. In fact, Amantadine is the only compound used in patients, but it has limited efficacy and side effects. There is, therefore, a high need for improved pharmacological treatment that can control dyskinesia while leaving intact the therapeutic effect of L-DOPA.
According to our preliminary results, the proposed combined therapies are expected to produce improved antidyskinetic effects, and amelioration of motor symptoms. The advantage of this approach relies on the fact that medications in advanced stage of clinical development will be used. Therefore, this project may rapidly lead to clinical application of the findings.
The glutamate, serotonin and adenosine systems are interesting targets for pharmacological therapies in Parkinsonīs disease. However, interventions addressed at single systems have so far produced limited results. Indeed, the alterations induced in the human brain by the loss of dopamine neurons are complex and affect the function of several brain systems. In this project we attempted to counteract dyskinesia by pharmacological co-targeting of the above systems, in two pre-clinical models of dyskinesia. Results showed that combination of an adenosine A2A antagonist with a serotonin 1A/1B agonist produced better control of dyskinesia and motor symptoms compared to single drug administration. Given the late stage of development of the compounds that have been tested, the combination approach may lead to immediate clinical application of the findings.
INSERM Research Director at Institute of Neurodegenerative Diseases, CNRS UMR 5293, University Victor Segalen
Location: Bordeaux, France
Location: Cagliari, Italy
Researcher at Department of Biomedical Science, University of Cagliari
Location: Cagliari, Italy